ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3699_3702dup (p.Leu1235fs) (rs193922343)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491958 SCV000580141 pathogenic Hereditary cancer-predisposing syndrome 2018-05-03 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000694262 SCV000822698 pathogenic Hereditary nonpolyposis colon cancer 2019-12-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1235Argfs*4) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with colorectal cancer (PMID: 24689082). ClinVar contains an entry for this variant (Variation ID: 218069). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781589 SCV000919755 likely pathogenic Lynch syndrome 2018-08-29 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3699_3702dupAGAA (p.Leu1235ArgfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Another variant, affecting the same nucleotide positions, and leading to a similar protein level change, c.3699_3702delAGAA (p.Lys1233fsX6) and several other truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3799_3800delAT (p.Met1267fsX7), c.3840_3846delGGAGACT (p.Glu1281fsX44), c.3939_3940dupTC (p.Gln1314fsX14)). The variant was absent in 246004 control chromosomes (gnomAD). The variant, c.3699_3702dupAGAA, has been reported in the literature in an individual affected with colorectal cancer (Hansen 2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202173 SCV000257274 likely pathogenic not provided no assertion criteria provided research

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